TROICA: Thrombolysis in Cardiac Arrest (2008)

“In patients with out-of-hospital cardiac arrest, the use of tenecteplase during cardiopulmonary resuscitation did not result in a significantly higher rate of survival to hospital discharge than did the use of placebo.”

— The TROICA Investigators

1. Publication Details

  • Trial Title: Thrombolysis during Resuscitation for Out-of-Hospital Cardiac Arrest.
  • Citation: Böttiger BW, Arntz HR, Chamberlain DA, et al; for the TROICA Trial Investigators. Thrombolysis during Resuscitation for Out-of-Hospital Cardiac Arrest. N Engl J Med. 2008;359(25):2651-2662. doi:10.1056/NEJMoa0805702.
  • Published: December 18, 2008, in The New England Journal of Medicine.
  • Author: Bernd W. Böttiger, M.D.
  • Funding: Boehringer Ingelheim.

2. Keywords

Cardiac Arrest, Out-of-Hospital Cardiac Arrest, Cardiopulmonary Resuscitation (CPR), Thrombolysis, Fibrinolysis, Tenecteplase, Pulmonary Embolism, Myocardial Infarction.

3. The Clinical Question

In adult patients with witnessed out-of-hospital cardiac arrest of presumed cardiac origin (Population), does the administration of the thrombolytic agent tenecteplase during CPR (Intervention) compared to placebo (Comparison) improve survival to hospital discharge (Outcome)?

4. Background and Rationale

  • Existing Knowledge: A substantial proportion of cardiac arrests are caused by acute myocardial infarction or massive pulmonary embolism. Thrombolytic therapy is effective for these conditions in patients with a circulation, but its role during active CPR was unknown.
  • Knowledge Gap: It was unclear if thrombolysis administered during CPR could dissolve the causative thrombus and improve outcomes, or if the risks of major bleeding in the context of CPR would outweigh any potential benefit. Previous studies were small and inconclusive.
  • Proposed Hypothesis: The authors hypothesized that thrombolysis with tenecteplase during CPR would improve survival in patients with out-of-hospital cardiac arrest.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, randomized, double-blind, placebo-controlled trial.
  • Setting: Prehospital emergency medical services and hospitals in six European countries.
  • Trial Period: Enrollment from October 2002 to March 2007.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with witnessed out-of-hospital cardiac arrest who remained in arrest despite at least 5 minutes of CPR.
    • Exclusion Criteria: Known terminal illness, known intracranial hemorrhage, active bleeding, or known contraindications to thrombolysis.
  • Intervention: A single intravenous bolus of tenecteplase (weight-adjusted dose).
  • Control: A matching placebo (saline) bolus.
  • Management Common to Both Groups: All patients received standard advanced cardiac life support (ACLS) during ongoing CPR.
  • Power and Sample Size: The trial was powered to detect a 5% absolute difference in the primary outcome, requiring 1000 patients.
  • Outcomes:
    • Primary Outcome: Survival to hospital discharge.
    • Secondary Outcomes: Included return of spontaneous circulation (ROSC), survival to hospital admission, neurological outcome at discharge, and incidence of major bleeding.

6. Key Results

  • Enrollment and Baseline: 1050 patients were randomized (525 to tenecteplase, 525 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the rate of survival to hospital discharge between the tenecteplase and placebo groups (14.7% vs 17.0%; P=0.29).
  • Secondary Outcomes: There were no significant differences in the rates of ROSC, survival to admission, or favorable neurological outcome.
  • Adverse Events: The incidence of intracranial hemorrhage was significantly higher in the tenecteplase group than in the placebo group (2.1% vs 0.4%; P=0.01).

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The proportion of patients surviving to hospital discharge was compared between the two groups.
  • Key Statistic(s) Reported: Odds Ratio (OR) for survival to discharge with tenecteplase: 0.84 (95% CI, 0.60 to 1.18; P=0.32).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of survival in intervention group) / (Odds of survival in control group).
      • Calculation: The paper reports the OR as 0.84.
      • Clinical Meaning: An OR of 0.84 means there was a 16% lower odds of survival to discharge in the tenecteplase group compared to the placebo group, but this was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.60 to 1.18.
      • Clinical Meaning: This confidence interval is wide and crosses the line of no effect (1.0), indicating no statistically significant difference and a high degree of uncertainty. The true effect could be anywhere from a 40% harm to an 18% benefit.
    • P-value:
      • Calculation: The reported p-value was 0.32 (or 0.29 by chi-square).
      • Clinical Meaning: The p-value is well above the 0.05 threshold, confirming that the observed difference is likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 17.0% – 14.7% = 2.3%. This is an absolute risk increase of 2.3% for the outcome of death.
      • Clinical Meaning: The intervention was associated with a non-significant 2.3% absolute increase in the risk of death at hospital discharge.
    • Number Needed to Treat (NNT): Not applicable, as the intervention showed no benefit and trended towards harm.
  • Subgroup Analyses: No significant benefit was found in any of the pre-specified subgroups, including patients with a presumed pulmonary embolism.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, international, multicenter, randomized, double-blind, placebo-controlled trial, representing the highest level of evidence for an intervention during CPR.
  • Generalizability: The pragmatic inclusion of patients with witnessed out-of-hospital cardiac arrest increases the external validity of the findings.
  • Important Safety Data: The trial provided crucial data on the risks of thrombolysis during CPR, particularly the increased risk of intracranial hemorrhage.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The results apply to undifferentiated out-of-hospital cardiac arrest. The effect might be different in patients with a confirmed diagnosis of massive pulmonary embolism causing the arrest.
  • Other: The overall survival rate was low in both groups, which is typical for this condition but can make it difficult to detect a treatment effect.

10. Conclusion of the Authors

“The routine use of a thrombolytic agent during advanced life support for undifferentiated out-of-hospital cardiac arrest does not improve the outcome.”

11. To Summarize

  • Impact on Current Practice: This was a definitive “negative” trial that provided strong evidence against the routine, empiric use of thrombolysis during CPR for out-of-hospital cardiac arrest. It demonstrated a lack of benefit and a clear signal of harm (increased intracranial hemorrhage), leading to its removal from routine cardiac arrest algorithms.
  • Specific Recommendations:
    • Patient Selection: For adult patients with witnessed, undifferentiated out-of-hospital cardiac arrest.
    • Actionable Intervention: Do not routinely administer thrombolytic therapy during CPR.
    • Expected Benefit: No benefit in survival was demonstrated. Avoiding thrombolysis prevents an increased risk of intracranial hemorrhage.
  • What This Trial Does NOT Mean: This trial does not mean that thrombolysis should never be used in cardiac arrest. It may still be considered in highly selected cases where there is a strong clinical suspicion or confirmation of massive pulmonary embolism as the cause of the arrest.
  • Implementation Caveats: The findings provide a clear recommendation against a specific intervention in the vast majority of cardiac arrest cases.

12. Context and Related Studies

  • Building on Previous Evidence: The TROICA trial was designed to be the definitive study to confirm or refute the promising but inconclusive findings from case series and smaller, non-randomized studies.
  • Influence on Subsequent Research: As a large and robust negative trial, TROICA has largely settled this clinical question. Subsequent research has focused on other interventions during CPR and on the selective use of thrombolysis in patients with confirmed pulmonary embolism (e.g., the PEAPETT study).

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the true risk-benefit ratio of thrombolysis in the specific subgroup of patients with confirmed massive pulmonary embolism causing cardiac arrest?
  • Future Directions: Research continues to explore ways to improve outcomes from cardiac arrest, with a focus on high-quality CPR, post-resuscitation care, and targeted interventions for specific causes.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, testing a potentially life-saving but high-risk intervention for a common and devastating condition.
  • Methods: The study’s design was of the highest quality: a large, international, multicenter, double-blind, placebo-controlled RCT.
  • Results: The trial had a clear and definitive negative result for its primary endpoint of survival, with no signal of benefit in any secondary outcome or subgroup. Crucially, it also showed a significant increase in the risk of intracranial hemorrhage.
  • Conclusions and Applicability: The authors’ conclusion is a direct and unambiguous interpretation of the data. The results are highly applicable to prehospital and emergency care worldwide and have provided a strong evidence-based recommendation to abandon the routine use of this therapy.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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